tbuckley/cabot-search huggingface dataset:
Abstract LB137: Ovulatory years prior to menopause and postmenopausal endogenous hormone levels
Authors: Daniel W. Cramer, Allison F. Vitonis, Tianyi Huang, Amy L. Shafrir, Heather Eliassen, Robert L. Barbieri, Susan E. Hankinson
Journal: Cancer Research (2023)

Abstract Background: Estimated lifetime ovulatory years (LOY) is the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influence sex-hormone levels in postmenopausal women not using hormone therapy. Methods: Hormones, including estradiol and testosterone, were measured in 1976 postmenopausal women from the Nurses’ Health Study in plasma collected in 1990. Effects of age, years since menopause, body mass index (BMI), smoking status, and hysterectomy on hormone levels were assessed by t-tests and ANOVA. Multivariable linear regression was used to assess associations between LOY and hormones adjusted for potential confounders and the trend in hormone levels per 5-year increases in LOY estimated. Results: Women in the sample averaged: 61.4 years old at blood draw, 11.0 years since menopause, with a BMI of 25.8 kg/m2. 17.5% had a hysterectomy and 13.8% were current smokers. These characteristics were associated with one or more hormone levels and included as adjustment variables. Each 5-year increase in LOY was associated with a 6.0% increase in testosterone (95% CI 3.3%, 8.7%) in all women. In women with above-average BMI, each 5-year increase in LOY was associated with a 7.3% (3.5%, 11.2%) increase in testosterone, a 6.9% (2.7%,11.3%) increase in estradiol, and a 6.9% (2.9%,10.9%) increase in estrone. Conclusion: Greater LOY is associated with higher testosterone in postmenopausal women as well as greater estradiol in those with above-average BMI. This may be due to an accumulation of functioning stromal and thecal cells from repeated ovulation and peripheral conversion of testosterone. Citation Format: Daniel W. Cramer, Allison F. Vitonis, Tianyi Huang, Amy L. Shafrir, Heather Eliassen, Robert L. Barbieri, Susan E. Hankinson. Ovulatory years prior to menopause and postmenopausal endogenous hormone levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB137.
Abstract LB216: Discovery of BCG033, a novel anti-PTK7 x TROP2 bispecific antibody-drug conjugate with promising efficacy against triple-negative breast cancer
Authors: Sufei Yao, Chengzhang Shang, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of metastatic breast cancer incidence, and remains an area of unmet clinical need due to the low rates of overall survival. Recently, the TROP2-targeting ADC sacituzumab govitecan has received an accelerated approval from the FDA for adult patients with metastatic TNBC, as more than 85% of TNBC is marked by TROP2 overexpression. However, the clinical efficacy of ADC therapies targeting TROP2 alone is limited by its on-target toxicity. In an effort to offer therapeutic alternatives that limit this toxicity, we sought to identify other targets to combat metastatic TNBC in combination with TROP2. PTK7 is highly expressed in breast cancer; notably, PTK7 expression is higher in TNBC than non-TNBC, and is correlated with worse prognosis, tumor metastasis and TNBC progression. PTK7 has also been demonstrated to be enriched in tumor-initiating cells (TICs) in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs). We generated fully human anti-human PTK7 x TROP2 bispecific antibodies (bsAbs) from RenLite® mice, which harbor the complete human heavy chain immunoglobulin variable domain with a common human kappa light chain for subsequent bispecific antibody assembly. These bsAbs demonstrated reactivity to human, monkey, and dog antigens, and showed enhanced internalization in vitro compared with parental PTK7 antibodies. In addition, these bsAbs showed favorable tumor cell selectivity, as there was minimal internalization of the monovalent antibodies. These bsAbs were than conjugated with Monomethyl auristatin E (MMAE) to generate anti-PTK7 x TROP2 bispecific ADC (BCG033) candidates. BCG033 candidates showed potent anti-tumor activity in several cell line-derived xenografts including TNBC xenografts, indicating that BCG033 has strong therapeutic potential in TNBC and other PTK7/TROP2 co-expressing cancers. Patient-derived TNBC xenografts with co-expression of PTK7 and TROP2 have been screened for future in vivo drug efficacy screening. In summary, BCG033 has the potential to exert anti-tumor efficacy in TNBC and other solid tumors co-expressing PTK7 and TROP2. Citation Format: Sufei Yao, Chengzhang Shang, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. Discovery of BCG033, a novel anti-PTK7 x TROP2 bispecific antibody-drug conjugate with promising efficacy against triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB216.
Abstract LB177: Tumor sideomics: spatial characteristics and functional deregulation in colorectal cancer
Authors: Brandon Burgman, Xingxin Pan, S. Stephen Yi
Journal: Cancer Research (2023)

Abstract Clinical evidence suggests that right-sided colorectal cancer (CRC) tends to have a worse prognosis compared to left-sided CRC. The distinct functional mechanisms underlying this “sidedness” remain cryptic and poorly understood. Thus, molecular classification of CRC is of paramount in targeting specific subtypes and personalizing treatment for patients. To identify targetable molecular features to improve treatment regimens, we performed multi-faceted network analyses of hundreds of CRC patients. In our network model, epigenetic features, differential expression of transcript abundance, and mutational frequency were used to identify widespread gene dysregulation and perturbed pathways to reveal disrupted networks distinct to right or left sided colorectal cancer. We discovered histone related genes and distinct epigenetic signals are at play in right-sided CRC. Additionally, our studies reveal “at risk” patient characteristics suggestive of survival differences, to improve diagnostic predictors based on CRC sidedness. Overall, our integrative approach serves to link molecular profiles distinct between left and right sided colorectal cancer, while improving upon previous models of CRC and paving the way towards identifying more effective treatment alternatives from a previously overlooked, readily characterized subtype of colorectal cancer. Citation Format: Brandon Burgman, Xingxin Pan, S. Stephen Yi. Tumor sideomics: spatial characteristics and functional deregulation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB177.
Abstract LB195: Immunotherapies that repolarize macrophages and CD4 T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer
Authors: Samar Elorbany, Chiara Berlato, Larissa Carnevalli, Eleni Maniati, Jun Wang, Simon Barry, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill
Journal: Cancer Research (2023)

Abstract We asked if single-cell RNA sequencing (scRNA-seq) analysis of tumor immune cells in high-grade serous ovarian cancer (HGSOC) would reveal ways to enhance effects of neo-adjuvant chemotherapy (NACT). Analysis of 64,097 immune cells from seven HGSOC omental metastases showed that positive effects of NACT on immune responses were counterbalanced by induction of immunosuppressive mechanisms, especially related to antigen presentation and Treg activity. We identified stabilin-1 (Clever-1) on macrophages and FOXP3 in Tregs as targets and validated actions of their inhibitors in vitro. ScRNA-seq analysis of 69,781 cells from chemotherapy-treated syngeneic mouse HGSOC tumors showed significant agreement with the patient results. Combinations of chemotherapy with anti-stabilin1 antibody and/or FOXP3 inhibitor (AZD8701), FOXP3i, significantly increased median survival of mice with established peritoneal disease. Long-term survivors (300 days+) were resistant to tumor rechallenge. Analysis of bulk RNA sequencing data from treated murine tumors confirmed our hypothesis and suggested potential mechanisms to explain the anti-tumor response seen in the murine models. Tumors treated with chemotherapy plus anti-stabilin1 antibody showed significant enrichment of anti-tumor macrophage signature and antigen presentation pathway compared to chemotherapy alone. Tumors treated with chemotherapy plus FOXP3i in combination with anti-stabilin1 antibody showed significant upregulation of antigen presentation, T cell activation and cytotoxicity and T helper 1 differentiation pathways. There was significant reduction in FOXP3 positive cells and significant increase of Tbet positive cells in FOXP3i treated murine tumors suggesting repolarization of naive T cells in the tumor microenvironment towards a more anti-tumor T helper phenotype. As there are early phase clinical trials of FOXP3 inhibitor and anti-stabilin1 (Clever-1) antibody in patients with advanced cancer, these results suggest ways of improving response to chemotherapy not only in HGSOC but in other cancers that are treated by NACT. Citation Format: Samar Elorbany, Chiara Berlato, Larissa Carnevalli, Eleni Maniati, Jun Wang, Simon Barry, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill. Immunotherapies that repolarize macrophages and CD4 T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB195.
Abstract LB348: A controlled high fiber dietary intervention alters metabolome and gut microbiome in melanoma survivors
Authors: Yan Jiang
Journal: Cancer Research (2023)

Abstract Background: Multiple studies support the gut microbiome as playing a key role in response to immune checkpoint blockade (ICB). Habitual dietary fiber intake has been associated with improved response to ICB. We conducted a pilot feasibility study of a high-fiber dietary intervention (HFDI) in melanoma survivors. Methods: Melanoma survivors (BMI &amp;lt;40 kg/m2, currently not on active therapy) were enrolled to a 6-week controlled feeding study in which all meals were provided by MD Anderson Cancer Center Bionutrition Research Core. Target daily fiber intake was up to 50 g/day derived from whole foods. The primary outcome was compliance. Blood and stool were collected q 2 weeks. Whole genome shotgun sequencing (WGS) was performed on fecal specimens, and metabolomics was conducted using mass spectroscopy on blood and stool. Results: Ten participants were enrolled, of which 60% were female. Average BMI was 31.4 kg/m2, and average baseline fiber intake was 17.8 g/day (range 7.4-28.3 g/day). Overall compliance was 88% (95% CI 83%-93%) with 45.8 g/day fiber reached (range 40.0-50.0 g/day). HFDI was well-tolerated with 1 participant experiencing grade 2 diarrhea and all other AEs were grade 1: diarrhea (40%), bloating (50%), flatulence (60%) and abdominal pain (10%). Exploratory analyses of global and targeted metabolomics showed increases in the short chain fatty acid acetate, shifts in omega-3/6 PUFAs, and indole/tryptophan metabolism. Stool WGS analyses showed that the largest shifts in gut microbiome structure in those who started with the lowest baseline fiber intake. Conclusion: A HFDI is well-tolerated and feasible in a melanoma population. The expected shifts in metabolome and gut microbiome observed with HFDI support that participants were compliant. Thus, this intervention is currently being tested in a Phase II study in metastatic melanoma patients receiving ICB. Citation Format: Yan Jiang. A controlled high fiber dietary intervention alters metabolome and gut microbiome in melanoma survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB348.
Abstract CT238: Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor
Authors: Stephen Sunghan Yoo, Soohyeon Lee, Sangjoon Shin, Hyunjin Jung, David S. Hong
Journal: Cancer Research (2023)

Abstract A Phase I clinical trial is currently underway to test Nelmastobart (hSTC810), an antibody targeting butyrophilin 1A1 (BTN1A1), a novel immune checkpoint protein. This Phase I clinical trial is using a standard 3 + 3 escalation design to (i) explore safety, tolerability, dose-limiting toxicities, and pharmacokinetics, (ii) define a recommended Phase II dose, and (iii) evaluate preliminary efficacy in patients with advanced solid tumors. The current dose range for the clinical trial is 0.3 mg/kg to 15 mg/kg. Currently, all the dose levels have been completed without any dose-limiting toxicity having been observed. Here, we provide an update on the clinical trial data shown previously. First, we provide the results of the pharmacokinetics study of these patients for the selected doses and dosing intervals, including the peak plasma concentration (Cmax), the time to reach Cmax (tmax), and the average plasma concentration of hSTC810 over the dosing interval in steady state (Cavg). The change in cytokine expression and immune cell concentrations in patient blood samples were also analyzed. Specifically, a panel of cytokines was measured including IFN- γ, IL-2, IL-4, IL-6, IL-10, TNF-α, MCP-1, and TGF- β, while flow cytometry was used to detect a panel of immunological marker proteins including CD3, CD4, CD8, CD19, CD14, CD16, CD56, CD25, CD45. For pharmacokinetic studies, the concentrations of hSTC810 and anti-hSTC810 antibodies were quantified. Immunohistochemistry was performed on patient tumor biopsies that were stained for PD-L1, CD3, CD4, CD8, and BTN1A1 expression. The resultant slides were analyzed for PD-L1 tumor proportional score (TPS), PD-L1 combined positive score (CPS), BTN1A1 scoring, the percentage of CD3+ lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, tumor-infiltrating lymphocytes, and necrosis. Citation Format: Stephen Sunghan Yoo, Soohyeon Lee, Sangjoon Shin, Hyunjin Jung, David S. Hong. Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT238.
Abstract CT264: Taking sotorasib with an acidic beverage improves sotorasib exposure for subjects on omeprazole
Authors: Natasha Strydom, Panli Cardona, Marintan Spring, Jessica Purkis, Brett Houk
Journal: Cancer Research (2023)

Abstract The solubility of KRASG12C inhibitor sotorasib is pH dependent and coadministration with a proton pump inhibitor (omeprazole) decreased sotorasib maximum concentration (Cmax) by 56.9% and the area under the concentration curve from time zero to the time of the last quantifiable concentration (AUClast) by 42.4% under fasted conditions. This study in healthy volunteers evaluated if taking sotorasib with an acidic beverage such as Coca Cola would alter sotorasib absorption when coadministered with omeprazole and improve sotorasib exposure. Two separate phase 1, open-label, fixed sequence, 2-period studies enrolled at least 14 healthy subjects each. In the first study, each subject received a single 960 mg dose of sotorasib under fasted conditions on day 1, followed by omeprazole 40 mg once daily for 5 days on days 4 to 8, and then received omeprazole 40 mg in combination with sotorasib 960 mg on day 9 with water. For the second phase 1 study all conditions were kept the same except subjects received omeprazole in combination with sotorasib on day 9 with an 8-ounce (240 mL) glass of acidic beverage (Coca-Cola) instead of water. In both studies, intensive pharmacokinetic plasma sampling occurred predose and at 13 timepoints up to 48 hours post-dose. Sotorasib plasma concentrations were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. Non-compartmental analysis was used to calculate pharmacokinetic parameters. Safety and tolerability were monitored throughout the study. Increased sotorasib exposure was observed when sotorasib and omeprazole were taken with an acidic beverage compared to when sotorasib and omeprazole were taken with water for both AUClast (23200 vs 16700 h∙ng/mL respectively) and Cmax (4850 ng/mL vs 3110 ng/mL respectively). Compared to the geometric mean ratio of sotorasib and omeprazole taken with water, taking sotorasib and omeprazole with an acidic beverage resulted in an increase of 19.0 percentage-point in AUClast and a 24.6 percentage-point increase in Cmax. Coadministration of sotorasib and omeprazole with Coca Cola was safe and well tolerated. For patients on acid-reducing drugs, sotorasib taken with an acidic beverage is an effective strategy to increase sotorasib exposure and counteract the reduced exposures resulting from the drug-drug interaction effect of acid-reducing drugs. Citation Format: Natasha Strydom, Panli Cardona, Marintan Spring, Jessica Purkis, Brett Houk. Taking sotorasib with an acidic beverage improves sotorasib exposure for subjects on omeprazole [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT264.
Abstract CT267: ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial
Authors: Sumayah Jamal, Adnan Nagrial, Matteo Carlino, Rasha Cosman, Anthony Joshua, Richard Eek, Sarina Piha-Paul, Omid Hamid, Jenny Liu
Journal: Cancer Research (2023)

Abstract Programmed cell death 1 (PD-1) inhibitors have minimal effect in ovarian cancer (OC) and pancreatic ductal adenocarcinoma (PDAC). Selective endothelin B receptor (ETBR) blockade stimulates T cell tumor infiltration and synergizes with anti-PD-1 therapy in OC and PDAC mouse models. We are conducting an ongoing Phase Ib, open-label dose escalation study to assess the safety and tolerability of the selective ETBR antagonist ENB-003 (vodudeutentan) in combination with pembrolizumab in metastatic PDAC, OC and other advanced solid tumors (NCT04205227). The primary objectives are safety and tolerability. Secondary objectives include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Chemotherapy-resistant PDAC and platinum refractory/platinum resistant OC patients were microsatellite stable (MSS). The ENB-003 plus pembrolizumab combination was well tolerated across 6 dosing cohorts with no increase in toxicity above what is typically observed with pembrolizumab as a single agent. Encouraging preliminary efficacy signals have been observed. The DCR across 21 patients is 43% including 8 patients with stable disease (38%) and 1 (5%) with partial response (PR). The DCR for OC is 100% including 3 patients with stable disease (75%) and one MSS, PDL1 negative platinum refractory patient with a 95% PR (25%) of 12-month duration. In the current and final cohort, 3 PAC patients have been treated. One 4th line PDAC patient has exceeded 6-month survival (33%). We also observed a 7-month arrest of disease progression in a tonsillar SCC patient with innate resistance to anti-PD1. These data suggest that ETBR blockade is well tolerated, may expand the benefit of anti-PD1 in drug resistant solid tumors and warrants further study in subsequent trials. Citation Format: Sumayah Jamal, Adnan Nagrial, Matteo Carlino, Rasha Cosman, Anthony Joshua, Richard Eek, Sarina Piha-Paul, Omid Hamid, Jenny Liu. ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT267.
Abstract LB350: Novel mouse model to study HPV associated pathologies
Authors: Xue Li, Travis Schrank, Aditi Kothari, Hina Rehmani, Jason Tasoulas, Sulgi Kim, Wendell Yarbrough, Natalia Isaeva
Journal: Cancer Research (2023)

Abstract Papillomaviruses are species specific, non-enveloped, double-stranded DNA viruses that have an ~8kb circular genome enclosed by a 55 nm icosahedral capsid. Human papillomaviruses (HPV) are associated with both benign and malignant epithelial lesions. High-risk HPV subtypes are the causative agents of cervical and the majority of oropharyngeal squamous cell carcinomas. Persistent HPV infection is required for HPV-associated tumorigenesis; however, cellular factors needed to support the viral persistence and HPV genes expression are not completely understood. Several transgenic mouse models, developed in last decades, helped tremendously to study HPV-induced carcinogenesis. However, the absence of HPV non-coding upstream regulatory region and late coding region, as well as targeted early genes expression driven by an artificial promoter - features that are shared by all existent HPV transgenic mice - limit our ability to investigate HPV-associated malignant transformation and the role of host factors in this process. Therefore, we generated HPV16 transgenic mouse by using CRISPR/Cas9-mediated genome editing to insert the full-length HPV16 genome into the Rosa26 locus. Two founder mice, with single HPV copy and with tandem HPV integration, were used to establish mouse colonies. Interestingly, regardless of HPV copy number, ~30% of the HPV knock-in mice exhibited early death during the first 2 weeks after birth, while survived pups were significantly smaller than the same age wild-type mice, and had severe hair loss. Intriguingly, the growth retardant and hair loss phenotype in the HPV16 knock-in mice disappeared in ~4 weeks, most likely indicating that viral genes compromise specific stages of mouse development. We evaluated the expression of HPV genes during development, in different mouse organs, and in established fibroblasts and epithelial cell cultures. Our newly developed HPV16 knock-in mouse model provides viral gene expression from natural viral promoters offering an essential basis to explore the role of cellular factors in HPV-driven pathologies. Citation Format: Xue Li, Travis Schrank, Aditi Kothari, Hina Rehmani, Jason Tasoulas, Sulgi Kim, Wendell Yarbrough, Natalia Isaeva. Novel mouse model to study HPV associated pathologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB350.